This application claims the benefit of priority under 35 U.S.C. §119 of EP Application 05024898.8 filed Nov. 15, 2005, the contents of which are hereby incorporated by reference.
1. Field of the Invention
The present invention provides a method, an apparatus and a computer program to detect the liquid leakage of a liquid transfer device.
2. Description of Related Art
The increasing degree of automation and parallelization of industrial and scientific processes devotes high demands on the precision and reliability of robotics, especially based on the operational desire to optimize sample volumes and the time-to-result.
For the pharmaceutical industry and diagnostic applications said automation and parallelization concerns the handling of liquids like biological samples or reagents. A prominent example in this respect is the parallelization of PCR amplifications in a microtiter plate format with e.g. 386 or even 1536 individual reactions. To handle such a plurality of assays in a reasonable time frame automation is essential to transport reagents and samples to the microtiter plate.
Every PCR amplification comprises a number of individual preparation steps like lysis of cells, digestion, segregation and purification. Each of the individual preparation steps has to be controlled in order to avoid false overall results. With respect to the handling of liquids, it is important to control the amount of aspirated sample volume, to detect the leakage of the transfer device as well as the completeness of the dispensing process.
Especially the leakage control of the transfer devices is important not only because the amount of transferred liquid must be accurate, but also because a liquid leakage yields the risk of cross-contamination during the transfer process.
In the state of the art the drop surveillance as well as the aspiration/dispensing control is mostly performed by pressure monitoring of the liquid transfer device. WO 96/41200 discloses an automatic pipetting apparatus with leak detection based on a pressure sensor connected to the pipetting system to measure changes of the internal pressure in the pipetting system with time. U.S. Pat. No. 5,503,036 discloses a device and a method for determining whether a sample probe of an automated fluid sample aspiration/dispensing device is obstructed by measuring the pressure within said sample probe. EP 1066532 discloses a method and a device for drawing a biological sample using a manual or automatic suction-discharge device comprising means to detect pressure variations, whereas the pressure monitoring is used for a liquid level detection (LLD) in order to minimize the penetration depth of the device and the corresponding wetting of the outside walls of said device. WO 01/88549 claims a method for determining the quality of an aspiration process comprising the recording of a pressure curve. US 2001/14477 claims a system for dispensing precise quantities of a transfer liquid comprising the step of sensing a pressure change as measure for the volume of dispensed liquid. WO 02/73215 discloses the recording of a state variable during the aspiration and/or dispensing process of a liquid in order to display an evaluation result for the liquid dosing process.
Alternatively, the liquid handling can be supervised by electrical means. US 2001/49148 discloses a method of sampling compounds comprising the step of sensing an electrical signal that is indicative of contact between a solubilizing fluid within a capillary and compounds reversibly immobilized on a surface. JP 2003-172744 discloses a method to place liquid onto the surface of a substrate from the tip of a dropping section, wherein the electrostatic capacity between said substrate and said tip of the dropping section is measured in order to ensure that only droplets generated on the tip of the dropping section are brought into contact with the surface of the substrate.
In the state of the art for liquid handling, electrical means are also used for the liquid level detection (LLD) prior to the aspiration process and there are mainly two different approaches, the resistive LLD (rLLD) and the capacitive LLD (cLLD). Performing the rLLD, simply the electric resistance between the liquid transfer device and e.g. an electrode attached to the outside of the liquid transfer device is measured and the resistance will decrease significantly upon reaching the liquid level (e.g. U.S. Pat. No. 3,754,444). Performing the cLLD, the changes of the electric capacitance between the liquid transfer device and the vessel containing the liquid are monitored using an alternating voltage supply. There are different alternative embodiments of such a setup, e.g. the liquid transfer device itself is constructed as the first electrode and the vessel containing the liquid to be aspirated forms the second electrode. When the liquid transfer device is approaching the liquid level within said vessel, the capacitance will change (EP 164679, EP 355791, U.S. Pat. No. 4,818,492). A more sophisticated approach for a cLLD is disclosed in the EP 555710, wherein both electrodes are part of the liquid transfer device.